Exposure to low doses of ionizing radiation (LDR), both manmade and natural, constitutes a hazard for human health. Recent reports clearly demonstrate that there is a significant risk of LDR-induced health effects, including cancer, after medical procedures associated with LDR exposure, including radiation-induced leukemia and lymphoma. Little research has been conducted to determine the mechanisms by which the effects of LDR exposure are mediated. Detection of epigenetic alterations in tumors associated with occupational exposure to radiation suggests that epigenetics may contribute to IR-induced carcinogenesis. Our previous studies demonstrate that ionizing radiation (IR)-induced DNA methylation changes affect the hematopoietic tissue, including bone marrow (BM). However, it remains unknown in which population of BM cells changes in DNA methylation occur. Recent reports showed that persistent radiation-induced DNA damage is observed in hematopoietic stem cells (HSCs). Therefore, in the current proposal, we aim to elucidate the role of DNA methylation in the HSCs? response to LDR exposure. Particularly, in Specific Aim 1, we will identify whether exposure to LDR results in DNA methylation alterations in HSCs and determine the possible mechanisms of this response. In Specific Aim 2, we will elucidate whether differences in DNA methylation status predetermine the responses of HSCs to LDR. Specific Aim 3 is designed to determine if modification of DNA methylation in HSCs may alter their response to LDR. Successful completion of these Aims will allow us to determine the role of DNA methylation in HSCs? response to LDR. This knowledge will lead to a better understanding of the mechanisms of radiation-induced malignancies and will potentially lead to the discovery of pharmacological approaches for manipulating the effects of LDR exposure.